PROJECT SUMMARY In this application we propose a novel cellular therapy after autologous hemopoietic stem cell transplant (ASCT) for HIV related lymphoma (HRL) targeting multiple HIV antigens (gag, pol and nef) with the goal of depleting persistent HIV infection. In addition, we will also infuse T cells targeting EBV lymphoma associated antigens (LMP1, LMP2, EBNA1, BARF1) if the lymphoma is EBV positive. Investigators in both centers in this consortium have developed and optimized strategies to target EBV antigens which have shown promising results when infused post autograft to immunocompetent individuals with EBV+ lymphoma. More recently we have developed immunotherapy strategies to target HIV and in an ongoing study have safely infused autologous HIV specific T cells to HIV+ individuals with the goal of eradicating the virus reservoir. As antiretroviral therapy does not eliminate HIV in viral reservoirs and HIV+ individuals with lymphoma remain immunologically impaired we hypothesize that we can take advantage of the lympodepleted environment post ASCT to infuse autologous HIV specific T cells in a milieu that will promote expansion and persistence. Moreover, as nearly half of HRLis EBV positive we will infuse EBV specific T cells in this cohort with the goal of reducing the risk of relapse. In Aim 1 we will conduct a two arm Phase II clinical trial in which we will give HIV specific T cells to patients with HIV lymphoma early post autograft to all patients and will also give autologous EBV-specific T cells to patients with an HRL that is EBV+ve. In Aim 2, we will delineate the persistence and the anti-viral effects of the adoptively transferred T cells. The results of this study will inform approaches to eradicate the HIV reservoir and enhance immune function in patients with HIV related lymphomas. This strategy requires a multicenter trial due to the incidence of HIV lymphoma and our proposal is feasible since CTN has previously conducted a study of autograft in HIV lymphoma. Furthermore, our centers have extensive experience developing, implementing and completing complex biological therapies with cell and gene therapy products and have successfully sponsored and implemented over 100 cell and gene therapy studies under more than 50 investigator initiated INDs, including Phase II multicenter studies.